Rho, a low-molecule GTP-binding protein, is activated by signals from various cell membrane receptors.
The activated Rho functions, via Rho kinase signal transduction and actomyosin signal transduction, as a molecular switch for various cellular phenomena such as contraction of smooth muscles, morphological changes in cells, cell movement, cell division, intercellular adhesion, platelet aggregation, leukocyte aggregation, infiltration and increase of cancer cells.
It has been also known that such cellular phenomena deeply participate in diseases such as hypertension, angina pectoris, asthma, peripheral circulatory disorder, premature delivery, arteriosclerosis, cancer, inflammatory diseases, autoimmune diseases, AIDS, fertilization and implantation of a fertilized egg, osteoporosis, cerebral function disturbance, gastrointestinal dysfunction by bacteria, glaucoma and retinopathy.
Accordingly, it is believed that, when Rho is inhibited, prevention and/or treatment of the aforementioned diseases in which Rho is participated are/is possible.
On the other hand, it has been also known that, when Rho kinase, which exists in the downstream of signal transduction mediated by Rho, is inhibited, various cellular phenomena caused by Rho are able to be suppressed.
Thus, compounds which inhibit the Rho kinase are believed to be effective preventive and/or treating agents for the aforementioned diseases in which Rho is participated such as hypertension, angina pectoris, asthma, peripheral circular disorder, premature delivery, arteriosclerosis, cancer, inflammatory diseases, autoimmune diseases, AIDS, fertilization and implantation of fertilized egg, osteoporosis, cerebral function disturbance, gastrointestinal dyfunction by bacteria, glaucoma and retinopathy (WO 98/06433).
A Rho kinase inhibitor is usually defined as an inhibitor for serine/threonine kinase activated as a result of activation of Rho. The Rho kinase inhibitor includes compounds which inhibit protein having serine/threonine kinase activity such as ROKα (ROCK-II), ROKβ (ROCK-I, p160ROCK) and others.
Examples of the known Rho kinase inhibitor are amide derivatives disclosed in WO 98/06433; isoquinoline sulfonyl derivatives disclosed in WO 97/23222, Nature 389, 990-994 (1997) and WO 99/64011; heterocyclic amino derivatives disclosed in WO 01/56988; indazole derivatives disclosed in WO 02/100833; and quinazoline derivatives disclosed in WO 02/076976 and WO 02/076977.
It has been also disclosed in WO 00/09162 and WO 00/57914 that a Rho kinase inhibitor is useful as a treating agent for glaucoma.
However, in any of the aforementioned documents, there is no specific disclosure for the indazole derivative according to the present invention.